Process for treating neuroendocrinopathic diseases employing pimozide

ABSTRACT

Endocrinopathic diseases induced by hypothalamic hyperfunction are amenable to treatment by Pimozide and Fluspiriline. Specifically, the clinical manifestations of lipodystrophic diabetes are alleviated by administration of either 1-(-(4,4-bis(p-fluorophenyl)butyl)-4-piperidyl)-2-benzimidazolinone or 8(4,4-bis(p-fluorophenyl)butyl)-1-phenyl-1,3,8-triazaspiro(4.5)decan-4-one to a patient suffering from the disease.

United States Patent n 1 Corbin PROCESS FOR TREATING NEUROENDOCRINOPATHIC DISEASES EMPLOYING PlMOZlDE [75] Inventor: Alan Corbin, King of Prussia, Pa.

[73] Assignee: American Home Products Corporation, New York, NY.

[22] Filed: June 28, I973 [2l] Appl. No.: 374,454

[52] U.S. Cl. 424/267 [5]] Int. Cl A61k 27/00 [58] Field of Search 424/267 [56] References Cited OTHER PUBLICATIONS Jannssen et al., J. Clinical Pharm., Vol. I2 (I), pp.

[ Jan. 28, 1975 Primary Examiner-Vincent D. Turner Attorney, Agent, or Firm-Richard K. Jackson [57] ABSTRACT Endocrinopathic diseases induced by hypothalamic hypcrfunction are amenable to treatment by Pimozide and Fluspiriline. Specifically, the clinical manifestations of lipodystrophic diabetes are alleviated by administration of either l-{-[4,4-bis-(p-fluorophenyl) butyll-4-piperidyl}-2-benzimidaz0lin0ne or 8-[4,4- bis(p-flu0rophenyl)butyl I- I -pheny|-l ,3 ,8-triazaspiro- (4.5)decan-4-one to a patient suffering from the discase.

6 Claims, 2 Drawing Figures PROCESS FOR TREATING NEUROENDOCRINOPATHlCDISEASES EMPLOYING PlMOZlDE BACKGROUND OF THE lNVENTlON Various endocrinopathies, in which hypothalamic hyperfunction appears to be the prime cause of the endocrinopathology observed. are lipodystrophic diabetes, diabetes mellitus, acromegaly, ,Cushing's syndrome, Nelson's syndrone, Albright's syndrome. precocious puberty etc.

Exemplary of endocrinopathy is lipodystrophic diabetes, a rare and bizarre genetically transferred disease characterized by loss of subcutaneous and other body fat, skeletal and muscle over growth, splenomegaly and hepatomegaly due to fat infiltration, genital enlargement, hyperpigmentation with acanthosis nigricans, insulin-resistant hyperglycemia, hyperlipemia and hyperinsulinemia. Patients suffering from lipodystrophic diabetes, as opposed to normal subjects, exhibit detectable activities of releasing factors (corticotropin releasing factor CRF, follicle stimulating hormone releasing factor FRF, melanocyte stimulating hormone releasing factor MRF and luteinizing hormone releasing factor LRF) in their peripheral plasma. It has been established that CRF, FRF and LRF are present inperipheral plasma of ahypophysectomized human and that CRF, FRF and LRF are detectable in the peripheral plasma of hypophysectomized rats. l-leretofore, there has been no known effective treatment of patients suffering from lipodystrophic diabetes.

The compound {-1- 4,4-bis(p-fluorophenyl)butyl]4-piperidyl}2- benzimidazolinone is a known neuroleptic agent (J. Clinical Pharm., vol. 12 (1) pp. 26-34 (1972), commonly referred to as Pimozide, and presents the structure Likewise, the analogue 8-[4,4-bis(pfluorophenyl)butyl]-l-phenyl-l,3,6-triazaspiro (4.5)decan-4-one, is a known compound commonly referred to as Fluspiriline, which presents the structure DESCRIPTION OF THE INVENTION In accordance with this invention. there is provided a method for alleviating the clinical manifestations of endocrinopathies induced by hypothalamic hyperfunction which comprises administering an effective amount of either 1-- {-l-[4,4-bis(p-fluorophenyl)butyll-4-piperidyll-Z- benzimidazolinone or 8-l4.4-bis(p-fluorophenyl )butyll-phenyll ,3,8triazaspiro(4.5)decan-4-one to an afflicted patient.

More specifically there is provided a method for alleviating the clinical manifestations oflipodystrophic diabetes which comprises administering an effective amount of either 1-- {-l-[4,4-bis(p-fluorophenyl)butyl]-4-piperidyl}-2- benzimidazolinone or 8-[4,4-bis(pfluorophenyl)butyl l -phenyl-l ,3,8-triazaspiro( 4.5 decan-4-one to an afflicted patient.

By an effective amount, applicant intends to embrace that amount of the active ingredient which is necessary to cause regression of the observable physical and blood chemistry manifestations of the disease. ln practice, a dosage of 8.0 milligrams per day, administered orally, chronically, has been found to be effective in the treatment of lipodystrophic diabetes. Thus, depending upon the advancement stage of the disease and the gen eral physical condition and age of the patient, control of the disease is obtained by oral administration of 8.0 milligrams at intervals within the range of from 16 to 48 hours, chronically. Of course, the size of an individual dose as well as the regimen may be varied to achieve the desired results by the attending physician. In general, the dosage range for treatment of endocrinopathic diseases induced by hypothalamic hyperfunction is the same as that employed for the treatment of schizophrenia, or from about 4 to about 16 milligrams per day.

Both Pimozide and Fluspiriline may be administered orally or parenterally as neat or pure compounds without additives other than for purposes of providing suitable pharmaceutical solution or liquid suspension. However, conventional adjuvants known to the art may be combined with the active compounds of this invention to provide compositions and solutions if desired for producing tablets, capsules, injectables, and the like, without adverse effect upon the properties of the compounds.

The initial determination of the activity of Pimozide and Fluspiriline was conducted by the following test procedure, which is based upon the lack of any internal feed-back mechanism between the pituitary and hypothalamic functions in hypophysectomized rats. in essence, the presence of luteinizing hormonereleasing-factor in peripheral circulation of hypophysectomized rats, as opposed to intact rats, presents a dysfunction model in common with human patients suffering from lipodystrophic diabetes, for testing drugs which effect the hypothalamic releasing-factor mechanism. Thus, for example, a compound active in reducing the concentration of LH releasing-factor in peripheral circulation can be identified by observing the decrease of plasma LH increments in steroid-blocked ovariectomized rats treated with the plasma from the hypophysectomized rats.

The activity of Pimozide and Fluspiriline in reducing the concentration of luteinizing-hormone-releaserats which had been ovariectomized atleast 30 days prior to the study (200-250 grams initial body weight). Seventy-two hours prior to testing. the rats were blocked with.50 pg Estradiol Benzoate and 25 milligrams Progesterone in 0.25 milliliters corn oil. The change in luteinizing hormone in the recipient rats blood was determined in absolute level values by withdrawing an initial blood sample (1.0 ml.) from the anesthetized (ether) rat followed by a second blood sample (1.0 ml.) 20 minutes after administration of the peripheral plasma from the hypophysectomized female, Sprague-Dawley rat. The difference in luteinizing hormone content of the blood was determined from the preand post-treated assay rats and the data are expressed in terms of percentage change. The serum was assayed for luteinizing hormone according to the double antibody radioimmuno-assay procedure of G. N. Niswender et. al., Proc. Soc. Exp. Bio. Med., vol. 128, page 807 (1968). i

The accompanying FIG. 1 presents the results of the above described testing on a statistically significant number of standard experimental animals, the data for which is too voluminous to present in detail. In general the figure is self-explanatory, the vertical axis representing the percent change in luteinizing hormone found in the serum of the experimental animals. The first two bars of the graph represent the change observed upon administration of serum from normal (non-hypophysectomized) rats to the blocked, ovariectomized rats. The change in luteinizing hormone content of the recipient rats was quite small, demonstrating the absenceof any appreciable amount of LHRF in the serum of the intact donor rats. The third bar demonstrates a 450 per cent increase in the blood LH after administration of pure synthetic LHRF in an amount of l nanograms. The fourth bar demonstrates that the administration of serum from saline-treated hypophysectomized rats caused a 250 per cent increase in the concentration of LH in the blocked, ovariectomized rats. The final five bars summarize the data obtained upon administration of Pimozide and Fluspiriline in the stated amounts expressed in milligrams per kilogram body weight in conjunction with the same quantity of serum from hypophysectomized rats as was used in the fourth bar experiments. Thus, the data demonstrate a marked decrease in the quantity ofluteinizing hormone in the serum of the ovariectomized rats, indicating that administration of the two above named compounds reduces or eliminates the LHRF activity of the hypophysectomized animals.

To further demonstrate the effectiveness of the method of treating patients suffering from lipodystrophic diabetes, Pimozide was administered to an eight year old female patient (L.F.) presenting the classical clinical manifestation of the disease, for a period of eight months at a dose of 8.0 milligrams per day, orally, with a resulting demonstration of both objective and subjective improvement. Pimozide lowered the level of corticotropin-releasing factor and luteinizinghormone releasing factor in accordance with the data summarized in FIG. 2, which represents the results of the initial phase of the therapy trial. The CRF activity in the plasma of the patient was evaluated by the method of Arimura et. al., Endocrinology. 81,235 (1969) as modified by Upton and Amatruda, New England Journal of Med. 235 l96l p. 419. The LRF ac tivity was evaluated in the same manner as with the rat plasma discussed, supra.

The following table summarized the patients (L.F.) blood chemistry after about 9 months oftrcatment with Pimozide. demonstrating partial to complete normalization. ln the table. FSH means follicle stimulating hormone and LH means luteinizing hormone. SCOT means serum glutamic oxalic transaminase, and SGPT means serum glutamic pyruvate transaminase.

PLASMA CHEMISTRY OF PATIENT WITH LIPODYSTROPHIC DIABETES L.F.- Normal for L.F.-Prc Rx Pimozide Age & Scx

TOTAL LlPlDS g CHOLESTEROL g TRlGLYCERlDES (mg LlPEMlA (SERUM) TOTAL BlLlRUBlN (mg TRANSAMINASE 200 lll 2+ Clear Clear What is claimed is:

1. A process for reducing the activity of hypothalamic hypophysiotropic hormones in the blood plasma of an endocrinopathic patient which comprises chronically administering to a patient suffering therefrom. orally or parenterally, the compound 1-- {-1-[4,4-bis(p-fluorophenyl)butyl1-4-piperidyl1-2- benzimidazolinone, in an amount sufficient to alleviate the clinical characteristics of the endocrinopathy.

2. The process of claim 1 in which said compound is administered orally in an amount sufficient to at least partially normalize the activity of said hypophysiotropic hormones.

3. The process of claim 1 in which said compound is administered orally to said patient in an amount from about 4 to about 16 milligram per day, chronically.

4. A process for alleviating the clinical characteristics of the disease lipodystrophic diabetes which comprises chronically administering to a patient suffering from said disease, orally or parenterally, the compound 1-- {-l-[4,4-bis(p-fluorophenyl)butylj-4-piperidyll-2- benzimidazolinone in an amount sufficient to suppress the activity of the hypothalamic hypophysiotropic hormones in the blood plasma of said patient.

5. The process of claim 4 in which said compound is given orally at intervals from 16 hours to 48 hours in unit dosage form of from about 4 to about 16 milligrams.

6. The process of claim 5 in which said dosage unit is about 8.0 milligrams per day. 

2. The process of claim 1 in which said compound is administered orally in an amOunt sufficient to at least partially normalize the activity of said hypophysiotropic hormones.
 3. The process of claim 1 in which said compound is administered orally to said patient in an amount from about 4 to about 16 milligram per day, chronically.
 4. A process for alleviating the clinical characteristics of the disease lipodystrophic diabetes which comprises chronically administering to a patient suffering from said disease, orally or parenterally, the compound 1-(-1-(4,4-bis(p-fluorophenyl)butyl)-4-piperidyl)-2-benzimidazolinone in an amount sufficient to suppress the activity of the hypothalamic hypophysiotropic hormones in the blood plasma of said patient.
 5. The process of claim 4 in which said compound is given orally at intervals from 16 hours to 48 hours in unit dosage form of from about 4 to about 16 milligrams.
 6. The process of claim 5 in which said dosage unit is about 8.0 milligrams per day. 